Brunner, K; (2016) Early immunity to the Campylobacter genus - Insights into host and bacterial factors involved in health and disease. Doctoral thesis , UCL (University College London).

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Abstract

Human Campylobacter jejuni infection and disease manifestations include severe enterocolitis which is associated with a marked neutrophil influx. Disease severity varies between individuals and an increased risk of chronic gastrointestinal conditions is seen in the susceptible. Molecular events causative to neutrophil infiltration, subsequent bacterial interaction(s) and underlying host risk factors remain poorly understood. In this study we investigated neutrophil-mediated phagocytosis of C. jejuni. We found that bacterial internalisation by neutrophils was serum-dependent and identified complement-opsonins and complement receptor CR1 as a major driver of bacterial uptake. Phagocytosis was accompanied by a modest generation of neutrophil reactive oxygen species (ROS) but interestingly, we failed to observe bacterial clearance. Activation of the complement cascade by C. jejuni was recognised to be multifactorial. Evidence is provided that implicated the classical and/or alternative pathway whilst usage of the lectin-mediated complement activation may be limited. C. jejuni surface glycosylation may modulate complement activation as enhanced uptake and serum-mediated bactericidal activity was observed in a mutant strain lacking the polysaccharide capsule. Finally, we identified in parts the lipooligosaccharide (LOS) structure of C. concisus, a potential pathogenic member of the Campylobacter genus. Mass spectrometry indicated no evidence for the presence of sialic acid and phosphoethanolamine (PEA) in C. concisus LOS; this data is novel and is in contrast with the C. jejuni LOS structure where both, sialyation and phosphorylation, are considered important in promoting the TLR4 pro-inflammatory axis. In line with this, we observed lower levels of cytokine secretion by PBMCs in response to C. concisus when compared to C. jejuni and observed reduced virulence in a Galleria mellonella infection model. Taken together, the present study suggests a novel role for the complement system in bacterial-neutrophil interaction and highlights the importance of various bacterial and host factors in immunity to the Campylobacter genus.

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